The purpose of this proposal is to foster the scientific development and bench laboratory skills of Dr. Anne Fitzpatrick so that she may become an independent investigator with expertise in clinical translational research. Dr. Fitzpatrick's long-term goal is to identify novel biological mechanisms responsible for severe asthma in children. Steps integral to the attainment of this goal are: 1) to acquire the necessary bench laboratory skills that will enable her to conduct independent clinical translational experiments; and 2) to engage in multidisciplinary mechanistic studies of oxidant stress and alveolar macrophage (AM) function in children with asthma. This Research Career Award will allow Dr. Fitzpatrick to not only develops her research skills and expertise, but also to pursue a didactic phase of study, which is essential for her development into an independent investigator. The laboratories, clinical facilities, and academic environment at Emory University will provide Dr. Fitzpatrick with the ideal setting to investigate the biological and clinical impact of oxidant stress and AM maturation and function in children with severe asthma. Through collaboration with a laboratory science mentor (Dr. Lou Ann Brown), a clinical pediatric asthma specialist (Dr. W. Gerald Teague), and an extensive network of experienced scientific and clinical researchers, Dr. Fitzpatrick will obtain the foundation for the development of an independent academic research career. Severe asthma is a significant source of morbidity in children. Although the pathogenesis of severe asthma is unclear, symptoms are thought to result from persistent airway inflammation, with respiratory infections as a major trigger. The exact mechanisms linking severe asthma and the risk of respiratory infection are not well defined. Dr. Fitzpatrick has previously demonstrated that children with severe asthma have impaired AM function, which is restored with antioxidant (glutathione) supplementation. These data suggest that airway oxidative stress may directly inhibit AM function in children with severe asthma, a finding which may account for the increased risk of respiratory infection in this population. This proposal will test the hypothesis that severe asthma-induced inflammation and oxidant stress result in compromised AM function via impairment of AM macrophage maturation. Three aims will be tested: 1) whether children with severe asthma have airway inflammation and oxidant stress, which impair AM maturation; 2) whether AM maturation and function will be restored with the anti-inflammatory agent rosiglitizone; and 3) whether impaired AM function predicts respiratory infection and poor symptom control in children with severe asthma. The outcome of this proposal may impact patient care and clinical assessment, and will offer greater insight into the pathophysiology of severe asthma in children. This proposal will lay the foundation for further studies, and the mechanisms identified may ultimately be targeted in future interventional trials. [unreadable] [unreadable] [unreadable]